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Results for “Tumor Microenvironment”

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PubMed2026

OLFML2B promotes hepatocellular carcinoma malignancy via the PI3K/AKT-EMT axis and correlates with an immunosuppressive tumor microenvironment.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality, highlighting the need for novel biomarkers and therapeutic targets. METHODS: The role of Olfactomedin-like 2B (OLFML2B) in HCC was investigated through multi-database analyses (The Cancer Genome Atlas, International Cancer Genome Consortium, Gene Expression Omnibus) and experimental validation. RESULTS: OLFML2B was significantly upregulated in HCC tissues, correlated with poor overall and disease-specific survival, clinicopathological features (tumor grade, stage, age, gender), and robust diagnostic performance (AUC > 0.7 across 14/15 datasets). Transcriptomic and single-cell analyses further revealed that high OLFML2B expression was associated with an immunosuppressive tumor microenvironment, characterized by increased infiltration of M2 macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), as well as reduced abundance of cytotoxic T cells and NK cells. Knockdown of OLFML2B suppressed malignant phenotypes, including cell proliferation, migration, invasion, and angiogenesis, attenuated PI3K/AKT-EMT signaling, and enhanced sensitivity to sorafenib, cabozantinib, and regorafenib in Huh7 and HepG2 cells. Additionally, OLFML2B knockdown suppressed tumor growth and metastasis in zebrafish xenografts. DISCUSSION: Collectively, these findings indicate that OLFML2B is required for HCC progression and represents a prognostic biomarker and potential therapeutic target.

Humans↗

PubMed1985

T cell locomotion in the tumor microenvironment. I. A collagen-matrix assay.

Previous studies have shown that lymphocytic infiltrates of different mouse mammary tumors contain different proportions of the T cell subsets Lyt-1+ and Lyt-2+. These characteristic subset ratios may be established, at least in part, by differential locomotion of subsets in response to components of the tumor microenvironment, such as soluble chemotactic and chemokinetic factors, cell and stromal surfaces, oxygen tension, and pH. We describe a new in vitro assay for determining how such microenvironmental variables affect lymphocyte locomotion. Suspended lymph node cells, alone or mixed with other cell types, are sandwiched between two layers of type I collagen gel and bathed in culture medium. A halo of locomotory cells fans out around the flattened droplet. Locomotion requires energy and exogenous protein. After a 24-hr incubation at 37 degrees C, 10% CO2 in air, the cell density of the halo is analyzed optically and the subset ratios are characterized by immunofluorescence staining of the gel sandwich. Under standard culture conditions, the locomotory population is enriched 12% in Thy-1+ cells compared with the bulk population, and the ratio of Lyt-1+ to Lyt-2+ cells is significantly increased. Lymphocyte locomotion is inhibited by 1 microM PGE2, by decreased pH and oxygen tension, and by the presence of normal mammary cells or mammary adenocarcinoma cells. The Lyt-1+:2+ ratio in the locomotory population is not altered by PGE2 but is reduced by acidity and hypoxia. The ratio is also reduced by the presence of mammary cells and cells of one of the mammary adenocarcinoma cell lines tested (168) but not by two others (68H and 410). Our data support the hypothesis that the locomotion of T cell subsets is differentially responsive to the types of microenvironmental conditions that vary among tumors.

Animals↗

PubMed2026

Activating mutations in ESR1 contribute to an immunosuppressive breast tumor microenvironment by dampening cytokine secretion.

Patients with estrogen receptor+ (ER+, ESR1+) breast cancer are most at risk of relapse, where activating mutations in ESR1 promote metastasis and therapeutic resistance. These patients are also disadvantaged in responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a transgenic mouse model carrying either Y541S or D542G mutation in ESR1, mirroring the 2 most common mutations seen in patients. ESR1mut tumors do not differ in the total number of immune cells yet display downregulation in immune pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1β. T cells and macrophages have lower IFN-γ and antigen presentation, respectively. Mechanistically, ESR1mut negatively regulates immune modulator expression and upregulates Stat5 to dampen cytokine expression. In concordance, validation on ESR1mut patient tumors shows decreased IL-17a and IL-1β. Collectively, our findings reveal that ESR1 mutations contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity.

Animals↗

PubMedDate not supplied

Tumor microenvironment: what have we learned studying the immune response in this puzzling battlefield?

Recent developments hallmark the progress in the understanding of tumor immunology and related therapeutic strategies. The administration of interleukin-2 (IL-2) to patients with cancer has shown that immune manipulation can mediate the regression of established cancers. The identification of the genes encoding cancer antigens and the development of means for effectively immunizing against these antigens has opened new avenues for the development of active immunization of patients with cancer. However, an efficient immune response against tumor comprises an intricate molecular network still poorly understood. Only when the code governing immune responsiveness of cancer will be deciphered, new therapeutic strategies could be designed to fit biologically defined mechanisms of immune rejection of cancer. In this review, we propose that the mechanisms regulating tumor rejection in response to vaccination will be more efficiently identified by following the evolution of treatment induced events within the tumor microenvironment taking advantage of recently developed technological tools. As a model, we will discuss the observed immune response to tumor antigen -specific immunization and its relationship with the systemic administration of IL-2.

Animals↗

PubMed1995

Prostaglandins and gangliosides of tumor microenvironment: their role in angiogenesis.

In the solid tumor the microenvironment is the space limited by the basement membrane of the microvessels and the neoplastic cells membrane. It includes the stroma and a liquid phase, the tumor interstitial fluid (TIF). We developed a method to sample TIF in vivo and found it rich in prostaglandins. In the rabbit cornea PGE1 induces neovascularization and acts as an angiogenesis factor. Before angiogenesis appears the ganglioside content of the cornea doubles with sharp reduction of the GM3/GD3 ratio. These gangliosides are not angiogenic but they influence the endothelial cell behavior. In particular when the PGE1 dose is insufficient to induce angiogenesis, enrichment of corneal tissue with GD3 or GM1 stimulates angiogenesis. However, when the corneal tissue is enriched with GM3, doses of PGE1, normally angiogenic fail to do so. The same was observed when bFGF substituted PGE1 as an angiogenesis trigger. The gangliosides tested acted as modulators of the angiogenic response by promoting the angiogenic capacity of molecules, such as PGE1 or bFGF, normally present in the tissue microenvironment. Several neoplastic cells, especially melanomas, shed gangliosides in the microenvironment. Their modulatory effect on angiogenesis may influence metastatic and/or primary tumor growth.

Alprostadil↗

PubMed2002

Interrelationships among angiogenesis, proliferation, and apoptosis in the tumor microenvironment during N-methyl-N-nitrosourea androgen-induced prostate carcinogenesis in rats.

Proliferation, apoptosis and angiogenesis are critical biologic processes altered during carcinogenesis. Surrogate biomarkers of these processes represent potential intermediate endpoints for short-term intervention studies with preventive and therapeutic agents. We examined the interrelationships among these processes during prostate carcinogenesis induced by N-methyl-N-nitrosourea (MNU) in male Wistar-Unilever rats. Immunohistochemical and digital image analysis techniques were used to evaluate the proliferation index, the apoptotic index and microvessel density (MVD) in tissue representing stages of prostate carcinogenesis. The proliferation index in the normal glandular epithelium of the prostate is lower than that observed in hyperplastic foci and atypical hyperplasia (P < 0.01) and is further increased in carcinoma (P < 0.01). Apoptosis in the normal prostate epithelium or hyperplastic lesions is lower than in adenocarcinoma (P < 0.01). In parallel to proliferation index, MVD increases as prostate cancer progresses. As tumors enlarge, we observed a predictable change in biomarker expression within the tumor microenvironment. We examined prostate tumors vertical line 1 cm in diameter and biomarker expression was quantified within the peripheral (outer 1-2 mm), central (perinecrotic) and intermediate (remaining) areas of each tumor. The proliferation index is higher (P < 0.01) in the intermediate area than either in the peripheral area or central area. Similarly, the vascular density in the intermediate area is higher (P < 0.01) than either in the peripheral or central area. The apoptotic index is higher (P < 0.05) in the central perinecrotic core than that in either the intermediate or the peripheral area. In conclusion, we observe that angiogenesis, proliferation and apoptosis are linked biological processes predictably altered temporally and spatially during prostate carcinogenesis in the MNU model. These biomarker changes are similar to those reported in human prostate carcinogenesis and represent potential biomarkers for the assessment of dietary, chemopreventive and therapeutic agents.

Androgens↗

PubMed2026

Hypoxia Response Is Associated with Reduced HPV Activity and Tumor Microenvironment Remodeling in Cervical Cancer.

Human papillomavirus (HPV) significantly influences cervical cancer progression and treatment, yet its interactions with the tumor microenvironment remain incompletely understood. We performed single-cell and spatial transcriptomic sequencing on cervical cancer samples to explore these interactions. By aligning sequencing reads to a merged HPV16-human reference genome, we characterized HPV16 heterogeneity and its association with host states at the single-cell and single-gene levels. E5 transcriptional activity was negatively associated with the host interferon response, indicating a role in immune evasion. A hypoxic environment was correlated with the downregulation of E5 activity and elevated MHC-I expression, which may contribute to stronger interactions between hypoxic cancer cells and cytotoxic CD8⁺ T cells. Additionally, HPV16 integration in host cells was associated with increased fatty acid metabolism. These findings suggest that combining anti-angiogenic drugs and fatty acid metabolism inhibitors has the potential to improve cervical cancer treatment.

Cervical cancer↗

PubMed2025

Integrative multi-omics profiling deciphers tumor microenvironment heterogeneity and immunotherapy vulnerabilities in lung neuroendocrine carcinomas.

INTRODUCTION: Lung neuroendocrine carcinomas (Lu-NECs) are rare, highly aggressive lung tumors with poor prognosis and limited therapeutic options. Understanding the tumor immune microenvironment (TIME) is crucial towards personalized therapeutic strategies. OBJECTIVES: This study aims to systematically characterize the heterogeneity and complexity of the TIME in Lu-NECs by integrating proteomic, transcriptomic, and genomic data. METHODS: We performed comprehensive immune-proteomic profiling of 76 Lu-NECs across diverse histopathological subtypes to elucidate intra-tumoral TIME heterogeneity at the proteomic level. Validation was conducted in multiple independent cohorts, including 112 Lu-NECs using immunohistochemistry, 147 Lu-NECs, and 17 small cell lung carcinoma samples using transcriptomics. We integrated proteomic, transcriptomic, genomic, and clinical data to assess molecular, immunological, and clinical features, as well as therapeutic vulnerabilities across different immune subtypes. RESULTS: We delineated the immuno-proteomic landscape of Lu-NECs and identified two major immuno-proteomic clusters with distinct immunological, molecular, and clinical characteristics. IPC1 was characterized by high immune cell infiltration, while IPC2 exhibited sparse immune cell presence. Genomic analysis revealed distinct mutational patterns, with IPC1 showing a higher incidence of APOBEC-associated mutation signatures and IPC2 being enriched for mutations associated with defective DNA mismatch repair and tobacco-related mutagens. Functional analyses indicated that IPC1 was related to immune and oncogenic signaling activity, whereas IPC2 was associated with cancer stemness and proliferation-related features. Furthermore, IPC1 and IPC2 demonstrated histological subtype-specific clinical benefits from postoperative chemotherapy. Finally, we developed a machine learning model (iPROM) to predict Lu-NECs immune classification and improve risk stratification, which was validated across multiple independent cohorts. CONCLUSIONS: This study advances the understanding of the tumor immune microenvironment in Lu-NECs through multi-omics characterization and highlights potential personalized therapeutic vulnerabilities tailored to the specific immune landscapes of Lu-NECs.

Humans↗

PubMed2006

The potential of the tumor microenvironment to influence Apo2L/TRAIL induced apoptosis.

Apo2L/TRAIL ligation of specific cell surface receptors (DR4 and DR5) induces apoptosis of many malignant cells with little effect on normal cells. This anti-tumor capability has been demonstrated using cell lines of many tumor types, both in vitro and in vivo when the cells are grown as xenografts. We have extended these studies to investigate the efficacy of Apo2L/TRAIL against patient tumor xenografts in SCID mice and found that the growth of many tumors, both of primary and metastatic origin, can be inhibited by Apo2L/TRAIL. The basis of resistance to Apo2L/TRAIL induced apoptosis in malignant cells and normal cells is not completely understood, but it is known that a variety of factors including hypoxia, MMPs and cytokines present in the tumor microenvironment can influence the response of malignant cells to Apo2L/TRAIL. Currently, the clinical potential of several molecules targeting the Apo2L/TRAIL receptors DR4 and DR5 is being investigated. Our goal in this review is to provide a brief overview of a number of factors that have potential to influence the response of patient tumors to Apo2L/TRAIL.

Animals↗

PubMed2006

Tumor microenvironment modulates hyaluronan expression: the lactate effect.

Hyaluronan (HA) synthesis is a tightly regulated process and is partly controlled by the microenvironment (e.g., lactate concentration). Experimental evidence has indicated that the melanoma cells that synthesize large amounts of HA exhibit enhanced tumor cell growth and increased metastatic capacity compared to those expressing smaller amounts. Because most studies have examined HA expression on melanoma cells in vitro, we compared the patterns of HA expression by B16-F1 and B16-F10 melanoma cells in vitro and in situ. Cell surface HA expression was assessed with the HA-binding peptide Pep-1. B16-F1 melanoma cells showed significantly higher levels of Pep-1 binding compared with B16-F10 cells in vitro. On the other hand, expression levels of HA were comparable between B16-F1 and B16-F10 melanoma cells in cryostat sections. These results show that B16-F1 cells express high levels of HA in vitro and in vivo, while B16-F10 cells express high concentrations of HA only in the context of skin tumors. Finally, B16-F10 melanoma cells, but not B16-F1 cells, expressed high concentrations of HA after stimulation with lactate. We propose that components of the tumor microenvironment (e.g., lactate) can induce melanoma cells to express HA and thus acquire an aggressive phenotype.

Animals↗

PubMed2006

Occurrence of thymosin beta4 in human breast cancer cells and in other cell types of the tumor microenvironment.

Previous studies have shown that the G-actin sequestering polypeptide thymosin beta4 frequently is overexpressed in cancers and that such overexpression correlates to malignant progression. However, the localization of thymosin beta4 in human cancers has not been determined. We now demonstrate that there is a considerable heterogeneity in the cellular distribution of thymosin beta4 in breast cancer. In most tumors examined, cancer cells showed low or intermediate reactivity for thymosin beta4, whereas leukocytes and macrophages showed intense reactivity. In addition, endothelial cells showed variable reactivity to thymosin beta4, whereas myofibroblasts were negative. There was no correlation between the intensity of tumor cell staining and histological grade, whereas there was a tendency toward a correlation between endothelial cell staining and grade. These results demonstrate that multiple cell types within the tumor microenvironment produce thymosin beta4 and that such expression varies from tumor to tumor. Such heterogeneity of expression should be taken into account when the role of thymosin beta4 in tumor biology is assessed.

Breast Neoplasms↗

PubMed2003

Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death.

The emergence of clinical drug resistance continues to be an obstacle for the successful treatment of cancer. Our current understanding of mechanisms associated with drug resistance has been ascertained by investigating drug-resistant models created by exposing a parental population to increasing concentrations of a cytotoxic. These unicellular drug-resistant models have been critical in elucidating drug-resistant mechanism and in some cases have aided in the identification of drug targets. However, these models do not address resistance mechanisms that contribute to de novo drug resistance. We propose that specific niches within the tumor microenvironment may provide a sanctuary for subpopulations of tumors cells that affords a survival advantage following initial drug exposure and may facilitate the acquisition of acquired drug resistance. More specifically, we propose that the bone marrow microenvironment is a sanctuary for hema-topoietic cancers. This review will focus on the bone marrow microenvironment and its role in conferring resistance to cytotoxics and physiological mediators of cell death.

Animals↗

PubMed1999

Mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is induced by low oxygen conditions found in solid tumor microenvironments. A candidate MKP for the inactivation of hypoxia-inducible stress-activated protein kinase/c-Jun N-terminal protein kinase activity.

Pathophysiological hypoxia is an important modulator of gene expression in solid tumors and other pathologic conditions. We observed that transcriptional activation of the c-jun proto-oncogene in hypoxic tumor cells correlates with phosphorylation of the ATF2 transcription factor. This finding suggested that hypoxic signals transmitted to c-jun involve protein kinases that target AP-1 complexes (c-Jun and ATF2) that bind to its promoter region. Stress-inducible protein kinases capable of activating c-jun expression include stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and p38 members of the mitogen-activated protein kinase (MAPK) superfamily of signaling molecules. To investigate the potential role of MAPKs in the regulation of c-jun by tumor hypoxia, we focused on the activation SAPK/JNKs in SiHa human squamous carcinoma cells. Here, we describe the transient activation of SAPK/JNKs by tumor-like hypoxia, and the concurrent transcriptional activation of MKP-1, a stress-inducible member of the MAPK phosphatase (MKP) family of dual specificity protein-tyrosine phosphatases. MKP-1 antagonizes SAPK/JNK activation in response to diverse environmental stresses. Together, these findings identify MKP-1 as a hypoxia-responsive gene and suggest a critical role in the regulation of SAPK/JNK activity in the tumor microenvironment.

Activating Transcription Factor 2↗

PubMed1998

Tumor microenvironment can restrict the effectiveness of activated antitumor lymphocytes.

Transgenic mice expressing the oncogene SV40 T antigen (Tag) in the insulin-producing beta cells of the pancreas develop islet cell carcinomas. Expression of the oncogene beginning in adult life leads to autoimmunity and lymphocytic infiltration of premalignant lesions. Nevertheless, Tag-expressing solid tumors escape the immune surveillance and are devoid of infiltrating lymphocytes. Attempting to elicit a tumor inflammatory response, we have both expressed a potent costimulator in oncogene-expressing beta cells and increased the abundance of reactive T cells. Coexpression of the costimulator B7.1 and the Tag oncoprotein leads to destruction of normal and premalignant islets and severe diabetes. Nevertheless, Tag+ tumors eventually develop, evidencing significantly reduced B7.1 expression and no infiltration. Another approach, whereby the abundance of reactive T cells was increased in double transgenic mice expressing Tag and a Tag-specific, CD4+-restricted T-cell receptor, was similarly unable to elicit tumor infiltration and destruction. Thus, neither costimulatory tumor cells nor hyperactivated antitumor lymphocytes were sufficient to produce an effective tumor immune response. In contrast, adoptive transfer of lymphocytes activated ex vivo did result in modest tumor infiltration with a limited induction of high endothelial venules on tumor vasculature, provided that T cells were transferred into irradiated recipients. However, adoptive transfer of ex vivo activated lymphocytes did not produce the dramatic inflammation seen in premalignant lesions. Thus, in addition to the parameters of activation and abundance of antitumor lymphocytes, the tumor microenvironment is evidently a critical parameter that can suppress lymphocyte extravasation and/or function inside tumors, likely in part via distinctive properties of the tumor vasculature.

Adenoma, Islet Cell↗

PubMed2002

Exploiting the differential production of angiogenic factors within the tumor microenvironment in the design of a novel vascular-targeted gene therapy-based approach to the treatment of cancer.

PURPOSE: The aim of this study is to explore a novel strategy through which the differential production of pro-angiogenic cytokines within the tumor microenvironment can be exploited as a means of selectively killing the vascular endothelial cells upon which the survival and growth of a tumor depend. METHODS AND MATERIALS: Adenoviral vectors encoding a chimeric cell surface receptor composed of the extracellular domain of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR fused in frame to the membrane spanning and cytoplasmic domain of Fas were constructed and used to transduce primary human endothelial cells in vitro. The apoptotic response of these cells induced upon ligation of the chimeric receptor with VEGF was determined by measuring caspase-3 activation, AnnexinV-FITC binding, and the release of glucose-6-phosphate dehydrogenase. RESULTS: The chimeric Flk-1/Fas protein is stable and expressed at high levels on the surface of adenovirally transduced cells. Upon the addition of exogenous VEGF, these cells undergo rapid apoptosis. CONCLUSIONS: Receptor/Fas chimeras that recognize and bind pro-angiogenic cytokines represent a novel means by which the signal transduction events normally triggered in vascular endothelial cells upon the binding of angiogenic cytokines may be redirected toward the induction of apoptotic cell death. It is proposed that these constructs will prove of value in the further development of safe and effective vascular-targeted gene therapy-based approaches to the treatment of cancer.

Adenoviridae↗

PubMed2005

DNA ploidy, cyclin D1, bcl-2 and lymphocytic infiltration of the tumor microenvironment as prognostic factors in laryngeal cancer patients.

The aim of this study was to evaluate correlations between DNA ploidy type, the immunostaining of cyclin D1, bcl-2 and the intensity of lymphocytic infiltration of the tumor microenvironment in relation to the histopathological G differentiation and pTNM classification. Thirty two patients were treated surgically for laryngeal cancer with total or partial laryngectomy in the Department of Otolaryngology Zabrze. The percentage of bcl-2 immunostaining was showed in 53% of the cases and was found to correlate with G differentiation and the patients' age. Cyclin D1 antigen stained positively in 24 cases (75%). Expression of cyclin D1 correlated with cancer stage. Cyclin D1 negative stain was found in T4-stage. DNA ploidy was examined in 19 cases. Aneuploidy was found in 5 cases only, while the rest were diploid. DNA ploidy value correlated with cyclin D1 expression. All paraffin sections were found to contain lymphocytic infiltrations of CD43 and CD45RO phenotype in the tumor front. Some cases showed high intensity of lymphocytic infiltrations of CD45RO phenotype. The intensity of CD43 lymphocytic infiltrations in the tumor front was related to the expression of cyclin D1 and bcl-2.

Adult↗

PubMed2002

Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma.

Regulatory T cells (T(reg)) that prevent autoimmune diseases by suppression of self-reactive T cells may also suppress the immune response against cancer. In mice, depletion of T(reg) by Ab therapy leads to more efficient tumor rejection. T(reg)-mediated suppression of antitumor immune responses may partly explain the poor clinical response to vaccine-based immunotherapy for human cancer. In this study, we measured the prevalence of T(reg) that coexpress CD4 and CD25 in the PBLs, tumor-infiltrating lymphocytes, and regional lymph node lymphocytes from 65 patients with either pancreas or breast cancer. In breast cancer patients (n = 35), pancreas cancer patients (n = 30), and normal donors (n = 35), the prevalence of T(reg) were 16.6% (SE 1.22), 13.2% (SE 1.13), and 8.6% (SE 0.71) of the total CD4(+) cells, respectively. The prevalence of T(reg) were significantly higher in breast cancer patients (p < 0.01) and pancreas cancer patients (p < 0.01) when compared with normal donors. In tumor-infiltrating lymphocytes and lymph node lymphocytes, the T(reg) prevalence were 20.2% (SE 3.93) and 20.1% (SE 4.3), respectively. T(reg) constitutively coexpressed CTLA-4 and CD45RO markers, and secreted TGF-beta and IL-10 but did not secrete IFN-gamma. When cocultured with activated CD8(+) cells or CD4(+)25(-) cells, T(reg) potently suppressed their proliferation and secretion of IFN-gamma. We conclude that the prevalence of T(reg) is increased in the peripheral blood as well as in the tumor microenvironment of patients with invasive breast or pancreas cancers. These T(reg) may mitigate the immune response against cancer, and may partly explain the poor immune response against tumor Ags.

Abatacept↗

PubMed2003

Impact of the tumor microenvironment on host infiltrating cells and the efficacy of flt3-ligand combination immunotherapy evaluated in a treatment model of mouse prostate cancer.

We have previously reported that Fms-like tyrosine kinase-3 ligand (flt3-L) induced tumor stabilization and regression of palpable ectopic prostate tumors (TRAMP-C1). Although some mice remained "tumor free" for several months following termination of therapy, tumors invariably reappeared and grew progressively in all animals. The lack of a curative response suggests that TRAMP-C1 tumors may inhibit the development of a flt3-L-induced anti-tumor immune response. Consistent with this view, we demonstrate herein that TRAMP-C1 tumors isolated from flt3-L treated animals contained a marked dendritic cell (DC) infiltrate that was temporally correlated with tumor regression. However, tumor-associated DCs, especially in a flt3-L setting, progressively lost MHC class II antigen expression during tumor growth. Treatment with the DC maturation factor trimeric CD40 ligand (CD40-L) either alone or in combination with fl3-L neither prevented loss of DC class II antigens nor disease relapse. Because loss of class II antigens would prevent CD4+ helper T (Th) cell development, we treated tumor-bearing mice with agonistic anti-4-1BB antibody (Ab), which can promote cytotoxic T lymphocyte (CTL) development independent of Th cell function. However, anti-4-1BB Ab alone did not alter TRAMP-C1 growth kinetics, and, when used in combination, was no more effective than flt3-L alone. The inability of the 4-1BB co-stimulatory signal to promote tumor regression may have been related to two additional features of TRAMP-C1 tumors. First, tumor-associated T cells, but not splenic T cells from tumor-bearing animals, were profoundly deficient in expression of CD3-epsilon (CD3epsilon) and T cell receptor-beta chain (TCRbeta). Second, CTLs required 24 h to efficiently kill TRAMP-C1 target cells even after up-regulation of MHC class I antigens by interferon-gamma. This rate of tumor cell destruction by CTLs may not be sufficient to prevent tumor progression. Taken together, these data reveal several important immunosuppressive characteristics of the prostate tumor microenvironment (TME) that immunotherapeutic interventions must first overcome to achieve longterm cures. These data also highlight the importance of utilizing treatment versus vaccination models in the evaluation of immunotherapeutic modalities.

Animals↗